Patients undergo video-EEG monitoring to determine seizure type and focus localization. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are used to study the functional anatomy of language and memory activation, cerebral metabolism, blood flow, binding to neurotransmitter receptors, deposition of inflammatory markers, alterations in blood-brain barrier permeability and structure. We found atypical language in 2.5% of healthy volunteers and 24.5% of patients. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning. Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for language mapping are functional MRI and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to optimize non-invasive language localization and assess its validity. We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed 4 language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether electrode pairs intersected with significant fMRI activity clusters for each language task. Sensitivity and specificity depended on electrode ROI radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description task provided the best tradeoff between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of ruling out language areas. 17 patients subsequently had temporal lobectomy. Four had postoperative language decline one year after surgery. Two of four had overlap of fMRI activated voxels, language positive electrodes in basal temporal regions (within 1cm), and resection. Two had overlap with fMRI activated voxels but not language positive electrodes. Patients who experienced language decline tended to have more fMRI activated voxels overlapping the resection than patients who did not. Age of seizure onset, resection side, resection type (standard anterior temporal lobectomy, amygdalohippocampectomy, or topectomy), resection volume, or seizure outcome at one year did not predict language decline. Language localization overlap of fMRI and direct cortical stimulation in resection influences postoperative language performance. Our preliminary study suggests fMRI may be more sensitive and less specific than direct cortical stimulation in predicting postoperative language outcome. fMRI and direct cortical stimulation together may predict postoperative language outcome after epilepsy surgery better than either test alone. Language fMRI is an effective tool for determining language lateralization prior to electrode implantation, and is especially useful for excluding unexpected critical language areas. In an additional study Using fMRI, we found a significant negative relationship between resected volume of the voxels within the top 10% of fMRI activation and BNT score change, with or without controlling for other potential factors, including resection volume, language LI, resection side dominance, and brain shrinkage after surgery. The amount of resected top 10% activation accounted for 20-25% of the variance in language naming ability decline. In a prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline. Four of 17 patients (12 female; median range age, 43 23-59 years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline.Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone. In collaboration with Dr Robert Innis in NIMH, we studied patients with ligands binding to the TSPO receptor, highly expressed on activated microglia and reactive astrocytes. We found that ligand binding was higher in TLE patients than in controls for all temporal regions ipsilateral to seizure foci and in contralateral hippocampus, amygdala, and temporal pole. This study shows that TSPO binding is increased both ipsilateral and contralateral to seizure foci in TLE patients, suggesting ongoing inflammation in epilepsy. Findings were most prominent in patients with MTS or FCD. In neocortical epilepsy, 9 of 11 patients had increased binding, showing focal and distributed inflammation. 3 had normal MRI. Anti-inflammatory therapy may have a role in treating drug-resistant epilepsy. We have conducted a series of studies of SSADH Deficiency, an autosomal recessive syndrome characterized by seizures, developmental delay, hypotonia, ataxia and neuropsychiatric symptoms. There is no treatment for this disorder. We initiated a trial of SGS-742, a GABA B receptor antagonist that has demonstrated good safety and tolerability in clinical trials of cognitive impairment, in patients age 8 years and older with SSADH deficiency. We will assess drug effects on cortical excitability using TMS as well as seizures, neuropsychological function, and other clinical parameters. The trial has been. completed and the data are being analyzed.